BackgroundSeveral small trials and many observational studies suggest that estrogen treatment in postmenopausal women improves cognition, but 2 large randomized trials have shown harm. The effect of an ultra–low- dose of unopposed transdermal estradiol on cognition and health-related quality of life is unknown.

ObjectiveTo investigate the effect of unopposed ultra–low-dose transdermal estradiol on cognitive function and quality of life in postmenopausal women.

DesignRandomized, placebo-controlled, double-blind trial with 2-year follow-up. The main outcome of the trial was change in bone density. Changes in cognitive function and quality of life were preplanned secondary outcomes of the trial.

SettingNine clinical centers in the United States.

ParticipantsPostmenopausal women (N = 417), aged 60 to 80 years, with a normal bone density for age and an intact uterus.

Main Outcome MeasuresSeven standardized cognitive tests (a total of 10 scores) administered at baseline and years 1 and 2 to test global cognitive function, verbal and visuospatial memory, language, executive function, and semantic memory. The 36-Item Short-Form General Health Survey was administered to assess health-related quality of life in physical and mental domains. The sample size provided 80% power to detect a standardized effect of 0.29 SD, a small-to-moderate difference.

ResultsBaseline characteristics were similar in the 2 treatment groups. At 2 years of follow-up, we found no statistically significant differences between treatment groups in change on any of the cognitive test scores or on the 36-Item Short-Form General Health Survey (P>.12 for all). There was no consistent evidence that the effect of treatment on change in cognitive or 36-Item Short-Form General Health Survey scores depended on the level of baseline endogenous estradiol.

ConclusionPostmenopausal treatment with ultra–low-dose unopposed transdermal estradiol for 2 years had no effect on change in cognitive function or in health-related quality of life over 2 years of treatment.

The most commonly used postmenopausal hormone therapy in the United States has been conjugated estrogens, at a dosage of 0.625 mg/d. However, several recent randomized trials1,2 have shown that harm outweighs the benefit of this standard dose of estrogen, either alone or in combination with progestins. Women are encouraged to take estrogen for short durations and to use the lowest effective dose.3

One of the unexpected results of the Women's Health Initiative Memory Study (WHIMS) was that women 65 years and older treated with conjugated estrogens (with and without progestins) had a higher risk of developing dementia and slightly more decline in global cognitive function scores compared with those assigned to placebo.4- 7 Similarly, the Heart and Estrogen/Progestin Replacement Study reported slightly worse cognitive function scores among women who had been treated with conjugated estrogens and progestin for 4 years compared with those assigned to placebo.8 These findings were in contrast to most prior observational studies9 that suggested a reduced risk of dementia and improved cognitive function in estrogen users compared with nonusers. One explanation for this discrepancy is that in observational studies the women who were taking estrogens were different from those not taking estrogens in ways that may have influenced the risk of developing dementia (eg, younger and more educated). Another possible explanation is that conjugated estrogens and estradiol may have differential effects on cognition and that there may be differences in outcomes depending on mode of delivery of estrogen (oral vs transdermal patch).10 The effect and safety of a very low dose of transdermal estradiol on cognitive function and health-related quality of life are unknown.

The goal of this study was to evaluate the effect of transdermal ultra–low-dose estradiol treatment on cognitive function and health-related quality of life in older postmenopausal women who were enrolled in a randomized trial of the effect of treatment on bone mineral density. In addition, we examined whether the effect of treatment on change in cognitive function and quality of life depended on the level of endogenous estradiol at baseline.

Methods

Design and participants

The Ultra–Low-Dose Transdermal Estrogen Assessment was a randomized, double-blind, placebo-controlled, 2-year trial conducted at 9 clinical centers in the United States. The main outcome was change in bone mineral density. The trial reported improvement in bone mineral density over 2 years at the lumbar spine (2.1% increase compared with placebo; 95% confidence interval, 1.3%-2.8%; P=.001) and at the total hip (1.2% increase compared with placebo; 95% confidence interval, 0.6%-1.8%; P<.001).11 Changes in cognition and health-related quality of life were preplanned secondary outcomes of the trial. The trial was coordinated at the University of California, San Francisco and was funded by Berlex Inc, the manufacturer of the transdermal estradiol patch (Menostar) used in this trial. Participants were women, aged 60 to 80 years, who had an intact uterus, were at least 5 years beyond menopause, and had a normal bone density for age (z score not <−2.0 at the lumbar spine).

Women were excluded from participating in the trial if they had unexplained uterine bleeding; endometrial hyperplasia or an endometrium greater than 5 mm in double thickness on transvaginal ultrasonography; an abnormal mammogram result suggestive of breast cancer; a history of metabolic bone disease; cancer (except nonmelanoma skin cancer); coronary disease, stroke, or a transient ischemic attack; venous thromboembolism; uncontrolled hypertension; uncontrolled thyroid disease; liver disease; a fasting triglyceride level greater than 300 mg/dL (>3.39 mmol/L) or a fasting glucose level greater than 180 mg/dL (>9.99 mmol/L); ever taken fluoride, calcitonin, or bisphosphonates; or taken estrogen or progestin within 3 months before randomization. The institutional review board of each clinical center and the coordinating center approved the study protocol, and informed consent was obtained from all participants.

Intervention

Participants were assigned to treatment in randomly permuted blocks of 4, stratified by clinical center, and all participants, investigators, and outcome assessors were blinded to treatment assignment. Treatment consisted of a 3.25-cm2-diameter estradiol patch or an identical placebo patch. The patch, delivering approximately 0.014 mg estradiol transdermally per day, was applied to a clean dry area of the abdomen once weekly. Patches that became detached could be replaced once during the 1-week period. All study participants received oral supplements of 400 mg of calcium twice daily and 400 IU of vitamin D once daily.

Baseline and follow-up measures

At baseline, we obtained information on demographics, health habits, health history, and medication use. Fasting blood tests included measurements of serum estradiol (double-antibody sequential radioimmunoassay [lower limit of detection, 1.4 pg/mL {5.14 pmol/L}]; Diagnostics Products Corporation, Los Angeles, Calif). Women were classified as having hot flushes if they reported that they had flushes at least some of the time during the prior week. At follow-up visits that occurred every 4 months during the trial, adherence was measured by patch counts and adverse events were ascertained.

Cognitive testing and health-related quality-of-life measures

All sites conducted cognitive testing. Staff who administered the cognitive tests were trained at a centralized training session to ensure uniformity in test administration and scoring. Seven cognitive tests (3 with 2 parts) assessing different domains were administered at baseline and at each annual follow-up. The Modified Mini-Mental State Examination (3MS) is a brief general cognitive battery with components for orientation, concentration, language, praxis, and immediate and delayed memory.12 Scores range from 0 to 100, with higher scores denoting better cognitive performance. Three tests of episodic memory (with a total of 6 scores) were administered: (1) Logical Memory Immediate and Delayed13 assesses the ability to remember a paragraph-long narrative shortly after and then 20 minutes after a recitation (the maximum score for immediate and delayed tests is 25), (2) Brief Visuospatial Memory Test (immediate with a maximum score of 36, and delayed with a maximum score of 12) assesses memory for 6 complex visual figures, and (3) Word List Memory assesses ability to remember 10 printed words on 3 separate trials, with a maximum score of 30, and Word List Recall tests ability to remember the same 10 printed words after a delay of about 10 minutes, with a maximum score of 10.14 Higher scores on each of the memory tests denote better performance. Trails B is a timed test of attention, visual scanning, and executive function. Scores are based on number of seconds required to complete the task, with lower scores denoting better cognitive function.15 The Modified Boston Naming Test is a 15-item test of language function that requires the subject to name objects presented in pictures. The test is scored based on the number of correct answers, with a maximum of 15.16 Verbal Fluency (Category Fluency) tests semantic memory, verbal production, and language. Scores are based on the number of animals named in 1 minute,14 such that higher scores denote better cognitive function. These tests were chosen because they are reproducible and valid measures16 that are similar to those that have been used in other large trials of postmenopausal hormone therapy, including WHIMS. Because depression can cause impaired cognitive function, participants also completed the Center for Epidemiological Studies–Depression Scale17 to assess depressed mood at cognitive function testing. All cognitive and depression scales were administered at baseline and at 1 and 2 years of follow-up.

Health-related quality of life was assessed at baseline with the self-administered Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).18 The SF-36 assesses physical and social functioning, limitations in role functioning due to physical and emotional problems, mental health, bodily pain, vitality, and general health perceptions. The 8 subscales are combined in 2 summary measures, the physical component scale and the mental component scale.

Statistical analyses

Baseline differences between treatment groups were assessed by using linear or logistic regression models, as appropriate, with adjustment for site. The primary analysis of treatment effects was by intention to treat, without regard to adherence. Changes in cognitive function and SF-36 scores were compared using mixed linear regression models, also with adjustment for site. The baseline, year 1, and year 2 outcomes were treated as repeated measures in this analysis, and treatment effects were estimated using a time × treatment interaction. In exploratory analysis, we found neither heterogeneity nor trend in the differences between groups and, thus, modeled time by an indicator for follow-up vs baseline. We also determined if treatment effect differed depending on a participant's baseline global cognitive score (based on a 3MS score of >90 or ≤90). To determine if there was an interaction between baseline estradiol level (using tertile) and treatment on cognitive function or health-related quality of life, we used linear contrasts in the estimated model coefficients to test for trend in treatment effects across tertile of estradiol. The sample of 417 provided 80% power (type I error rate of 5% and 2-sided tests) to detect between-group differences of 0.29 SD of change scores, a small-to-moderate difference. Confidence intervals for treatment effects were computed to help define the strength of negative findings. All analyses were performed using SAS statistical software, version 9.13 (SAS Institute Inc, Cary, NC).

Results

Between November 1999 and November 2000, 1509 women were screened for eligibility; 605 enrolled in a 1-week run-in phase, during which they received a placebo patch to wear to assess compliance with and tolerance to the transdermal system. During the run-in period, 10 women were excluded from the study because of noncompliance and 178 either were found ineligible or refused to continue screening11 (Figure). Thus, a total of 417 women eligible for participation in the study were randomly assigned to treatment with transdermal estradiol (n = 208) or placebo (n = 209).

Among women assigned to treatment with estradiol, 191 (91.8%) of 208 completed the trial compared with 185 (88.5%) of 209 in the placebo group (Figure). Reasons for withdrawing from the study were similar in the 2 treatment groups. Among women who completed the trial, 18 (9.4%) in the treatment group and 24 (13.0%) in the placebo group stopped taking the study medication before the end of the trial (P=.30). Among women who continued to use the study drug, patch counts showed that 84.3% used at least 75% of the expected number of patches during the entire 2 years of treatment and this percentage did not vary between the treatment groups.11

At baseline, the treatment groups were similar on a range of characteristics (Table 1). The mean (SD) age of participants at the beginning of the trial was 67 (5) years, 92.5% were white, and most (72.4%) had completed high school or a higher education. Of the 10 cognitive tests administered at baseline, most scores were statistically similar between treatment groups (Table 2). However, the mean scores for the 3MS and for Logical Memory Immediate and Delayed were slightly higher in the estradiol compared with placebo group at baseline (Table 2). Scores on the tests indicate, on average, a high level of cognitive function, with scores above age- and education-adjusted norms.14 Scores on the SF-36 physical and mental scales were similar across the 2 treatment groups (Table 2).

At baseline, the median plasma estradiol level was 4.8 pg/mL (17.62 pmol/L) and did not differ between treatment groups (Table 1). The median plasma estradiol level (obtained a mean of 3 days after patch change) in the estradiol group increased from 4.8 to 8.5 pg/mL (31.20 pmol/L) at 1 year and to 8.6 pg/mL (31.57 pmol/L) at 2 years (P<.001 vs baseline for both). The median plasma estradiol level in the placebo group decreased from 4.7 pg/mL (17.25 pmol/L) to 3.8 pg/mL (13.95 pmol/L) at 1 year (P<.001 vs baseline) and to 4.3 pg/mL (15.79 pmol/L) at 2 years (P<.02 vs baseline).

After 2 years of follow-up, we found no statistically significant between-group differences in change on cognitive test scores from baseline for any of the cognitive measures (Table 3). Confidence intervals for the between-group differences were narrow enough to rule out clinically important treatment effects on tests, including global function (3MS) and verbal memory (Logical Memory Delayed and Word List Recall) (Table 3). For example, beneficial effects on the 3MS score larger than 0.35 points and adverse effects larger than 0.70 points can be ruled out with 95% confidence. There was no difference in effect of treatment on women depending on baseline score on the 3MS (>90 or ≤90). Similarly, we found no treatment group differences for 2-year change on the SF-36 physical and mental scores (Table 3).

There was some evidence that the effect of treatment on the 3MS varied by tertile of baseline estradiol level (P=.05 for interaction). The effect of treatment among the women in the lowest tertile of baseline estradiol level was statistically different between the estradiol and placebo groups (P<.001), while treatment had no effect among women in the middle and upper tertiles of baseline estradiol level (Table 4). Among women in the lowest tertile of endogenous estradiol at baseline, 2 years of treatment with ultra–low-dose estradiol tended to worsen the score on the 3MS more than placebo. There was no interaction between baseline estradiol level and treatment on health-related quality-of-life scores (P>.27 for interaction for all).

Comment

We found that among postmenopausal women assigned to 2 years of treatment with an ultra–low-dose estradiol transdermal patch or placebo, there was no statistically significant difference on any of the cognitive test and health-related quality-of-life change scores between treatment groups. In addition, the effect of treatment on cognitive and SF-36 change scores was not consistently different in those women with a higher or those with a lower baseline endogenous estradiol level. To our knowledge, this is the first trial to investigate the effect of low-dose estradiol on quality of life and cognition in postmenopausal women.

In addition to many observational studies suggesting that estrogen may protect against the risk of developing cognitive impairment, several small randomized trials have suggested that estrogen therapy improves cognition in postmenopausal women without dementia.19- 22 However, most of these trials reported improved cognition in the estrogen-treated group, but did not compare these changes with the placebo group, making any suggestion of benefit unlikely.19,20,22 In addition, these trials enrolled women who were recently menopausal and likely to have menopausal symptoms, and it is possible that relief of insomnia or hot flushes with estrogen treatment might have resulted in the better concentration and cognitive performance observed in these women. Similarly, the literature23 on the effect of hormone therapy on health-related quality of life is conflicting with most studies, suggesting that improvements in quality of life are mediated by resolution of menopausal symptoms.

More recently, 2 large randomized trials of conjugated estrogens in older postmenopausal women who mostly were free from vasomotor symptoms reported that cognitive function was either similar or slightly worse in the hormone therapy group compared with the placebo group. In the Heart and Estrogen/Progestin Replacement Study,8 performance on 2 of 6 cognitive tests was slightly worse among women assigned to hormone therapy compared with women assigned to placebo. In WHIMS, women assigned to hormone therapy (conjugated estrogens with and without progestin) had less improvement in cognitive scores on a test of global function compared with those taking placebo.4,5

Some have suggested that the lack of a beneficial effect on cognition in the Heart and Estrogen/Progestin Replacement Study and WHIMS was because of the use of conjugated estrogens or the use of oral drug administration.10 While several trials24,25 of oral conjugated estrogens reported no benefit compared with placebo on cognition among women with Alzheimer disease, preliminary findings from a trial26 of transdermal estradiol suggest improved performance on some cognitive tests compared with placebo among women with Alzheimer disease. Our results do not support the hypothesis that transdermal estradiol, at least in ultra-low doses, improves cognitive function in postmenopausal women. However, our results should provide reassurance to women and to practitioners that ultra–low-dose estradiol taken for up to 2 years does not adversely affect cognition, at least in clinically significant amounts. Our finding of a lack of treatment effect on a measure of health-related quality of life is supported by results from the WHI, in which opposed and unopposed oral conjugated estrogens had no effect on a quality-of-life scale similar to the one we used.27,28

The strengths of our study include the use of a battery of sensitive and validated cognitive tests with measures for several cognitive domains, including verbal and visuospatial memory, global cognition, and executive function. Women enrolled in the trial were older and only approximately 16% had menopausal symptoms, making it unlikely that relief of these symptoms affects cognitive performance. In addition, we also measured serum estradiol level to determine whether women with a low baseline estradiol level might preferentially benefit from hormone therapy. Our results do not support this hypothesis.

Several limitations of our study deserve comment. Most of the Ultra–Low-Dose Transdermal Estrogen Assessment participants were white, and we do not know whether our findings generalize to other ethnic groups. We measured total estradiol level and it may be that bioavailable or free forms of estradiol better reflect levels available to the central nervous system.29 Women were at least 60 years old at enrollment in this trial and, thus, we cannot determine whether estradiol administered in the putative critical period during the perimenopausal years might have had a different effect. Finally, while we had good power to detect clinically significant differences in cognitive function by treatment group (≥0.29 SD), our power was less to detect smaller differences. The WHIMS had greater power to detect smaller effects and enrolled more women with low cognitive baseline scores, in whom estrogen was particularly harmful. While we did not find a difference in treatment effect depending on baseline 3MS score, we cannot be certain that our results apply to women with lower baseline cognitive scores.

Our results suggest that ultra–low-dose estradiol administered by a transdermal patch for 2 years had no effect on health-related quality of life and cognitive function in postmenopausal women. Prior analyses have reported that 2 years of treatment with unopposed ultra–low-dose transdermal estradiol improved bone density,11 but did not increase risk of uterine hyperplasia or cancer,30 urinary incontinence,31 or breast density.32 This information should be helpful in assessing the relative safety of ultra–low-dose transdermal estradiol vs standard-dose hormone therapy regimens.

Financial Disclosure: Within the past 5 years (aside from the grant support received for this study), Dr Yaffe has received grant support through the University of California, San Francisco, from Pfizer and Eli Lilly and has served as a consultant for Wyeth-Ayerst (all makers of estrogens or selective estrogen receptor modulators); Dr Ensrud has received grant support from Eli Lilly, Pfizer, and Bionovo; Dr Johnson has received grant support from Bionovo; Dr Diem has received grant support from Eli Lilly and Pfizer; and Dr Grady has received salary support via contracts with the University of California, San Francisco, from Berlex Inc, Eli Lilly, Merck, Pfizer, and Wyeth-Ayerst Research (all makers of estrogens or selective estrogen receptor modulators) and has received consulting fees for chairing a Data Safety Monitoring Board for Organon.

Funding/Support: This study was supported by Berlex Inc; and in part by grant R01 AG021918 from the National Institute on Aging (Dr Yaffe).